ADDITIVE AND SYNERGISTIC EFFECTS OF A LOW-MOLECULAR-WEIGHT, HEPARIN-LIKE MOLECULE AND LOW-DOSES OF CYCLOSPORINE IN PREVENTING ARTERIAL GRAFT-REJECTION IN RATS

Arteriosclerotic intimal proliferation is one of the main long-term complications of organ transplantation. Low-molecular-weight, heparin-like molecules prevent myointimal proliferation in arterial wall injury and limit rejection in skin allografts. Cyclosporin limits rejection but has no major effect on intimal proliferation. Therefore, an experimental protocol was designed to test whether heparin-like molecules interacted with low doses of cyclosporin to prevent arterial wall immune system injury and response in a model of arterial graft rejection in normotensive and hypertensive rats. Aortic allografts were performed in spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) normotensive control rats. Four groups of 10 allografted (SHR and WKY) rats were used: one group was treated with placebo, one with low doses of cyclosporin (2 mg/kg body wt per day), one with low-molecular-weight, heparin-like molecule (1 mg/kg body wt per hour), and one with low doses of cyclosporin plus low-molecular-weight, heparin-like molecule. Ten SHRs and 10 WKYs were isografted and served as the control groups. All rats were killed 8 weeks after aortic grafting. Structural parameters of the grafted segment were measured by morphometric analysis on formalin-fixed sections with specific stains. The classical signs of immune system injury and response were present in the untreated allografts in SHRs and WKYs: inflammatory infiltration of the adventitia, medial injury, and intimal proliferative response. Low doses of cyclosporin had a significant beneficial effect on immune medial injury by increasing medial thickness and the number of remaining smooth muscle cells and decreasing the extracellular matrix injury. Cyclosporin had no protective effect on intimal proliferation. Low-molecular-weight, heparin-like molecules had a beneficial effect on both the medial injury and the intimal proliferative response that was independent of blood pressure. Heparin-like molecules increased medial thickness and partially prevented smooth muscle cell loss and extracellular matrix attack. They also significantly decreased the intimal thickness by acting more on the collagen content than on the smooth muscle cell density. Low doses of cyclosporin plus heparin-like molecules had a marked effect in preventing the arterial wall injury and response. This combination resulted in a normal medial appearance, increased medial thickness and smooth muscle cell number, and no intimal proliferation or adventitial inflammation. Thus, heparin-like molecules appear to act in concert with low doses of cyclosporin in preventing rejection-induced arterial wall remodeling in an experimental model of aortic allograft in rats, and their effects are independent of blood pressure.